Antiphosphatidylserine Antibodies and Clinical Outcomes in Patients With Acute Ischemic Stroke

Xiaoqing Bu, MD; Hao Peng, MD, PhD; Chongke Zhong, MD; Tan Xu, MD, PhD; Tian Xu, MD, PhD; Yanbo Peng, MD, PhD; Chung-Shiuan Chen, MS; Jinchao Wang, MD; Zhong Ju, MD, PhD; Qunwei Li, MD; Deqin Geng, MD; Yingxian Sun, MD, PhD; Dongsheng Zhang, MD; Jintao Zhang, MD; Jing Chen, MD, MS; Yonghong Zhang, MD, PhD; Jiang He, MD, PhD

Disclosures

Stroke. 2016;47(11):2742-2748.

Abstract and Introduction

Abstract

Background and Purpose. Antiphosphatidylserine antibodies (aPS) have been associated with the risk of ischemic stroke. However, it remains unclear whether aPS will influence clinical outcomes in patients with acute ischemic stroke.

Methods. A total of 3013 patients with acute ischemic stroke recruited from 26 hospitals across China from August 2009 to May 2013 were included in the study The primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke. Secondary outcomes included death, major disability, recurrent stroke, and vascular events.

Results. Composite outcome of death and major disability rates were 29.1% versus 23.9% in aPS-positive and aPS-negative groups. Compared with aPS-negative, adjusted odds ratios or hazard ratios (95% confidence interval) associated with aPS-positive were 1.35 (1.07–1.71), 1.63 (0.99–2.69), and 1.25 (0.98–1.59) for composite outcome of death or major disability, death, and major disability, respectively. For 1 interquartile range increase of aPS, the adjusted odds ratios or hazard ratios were 1.10 (1.01–1.20), 1.19 (1.05–1.35), and 1.05 (0.96–1.14), respectively. Adding aPS status to a model containing conventional risk factors improved risk prediction for composite outcome of death or major disability (net reclassification improvement index=11.3%, P=0.006; integrated discrimination improvement=0.2%, P=0.04). There was no significant association between aPS and risks of recurrent stroke and vascular events.

Conclusions. We found that positive aPS increased risks of death or major disability at 3 months after an acute ischemic stroke, suggesting that aPS might be a prognostic marker for ischemic stroke.

Introduction

Stroke is the leading cause of death and disabilities worldwide.^[1] Biomarkers to identify patients at high risk of poor clinical outcomes would assist the selection of patients for aggressive monitoring and therapeutic interventions. Antiphospholipid antibodies (aPLs) are a heterogeneous family of antibodies to phospholipids and phospholipid-binding proteins.^[2] The presence of these antibodies is the laboratory feature of antiphopholipid syndrome, an autoimmune disorder characterized by susceptibility to vascular thromboembolism or fetal loss.^[3] Anticardiolipin antibodies (aCL) and lupus anticoagulant antibodies were the most frequently studied members and had been associated with an increased risk of recurrent thrombo-occlusive events and death after stroke in some but not in all studies.^[4–8] Recently, studies suggest that antibodies directed against phosphatidylserine (antiphosphatidylserine antibodies [aPS]) may be a useful marker for the syndrome.^[9–12] Population-based studies showed an independent association of aPS with ischemic stroke.^[13] However, it remains unclear whether aPS will influence stroke outcomes. We aimed to examine the association of aPS with clinical outcomes in a large cohort of patients with acute ischemic stroke.

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Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Baseline Characteristics of Participants According to aPS Status
Characteristics	aPS Negative (n=2362)	aPS Positive (n=651)	P Value
Age, y	61.5 (10.8)	63.8 (10.9)	<0.001
Male	1516 (64.0)	406 (62.4)	0.44
Time from onset to hospitalization, h*	10 (4–24)	11 (5–24)	0.74
Admission NIHSS score*	4 (2–8)	5 (3–8)	0.03
Admission NIHSS score >4	1145 (48.6)	349 (53.6)	0.02
Blood pressure at admission, mm Hg
Systolic	165.7 (16.9)	165.6 (16.2)	0.92
Diastolic	96.1 (11.0)	95.6 (10.9)	0.29
Body mass index, kg/m²	24.9 (3.1)	24.9 (3.2)	0.96
Current cigarette smoking	887 (37.6)	218 (33.5)	0.06
Current alcohol drinking	749 (31.7)	162 (24.9)	0.001
History of diseases
Hypertension	1871 (79.0)	502 (77.1)	0.30
Hyperlipidemia	174 (7.4)	47 (7.2)	0.90
Diabetes mellitus	437 (18.5)	103 (15.8)	0.11
Coronary heart disease	246 (10.4)	75 (11.5)	0.42
Ischemic stroke subtype†
Thrombotic	1838 (77.6)	492 (75.6)	0.27
Embolic	119 (5.0)	37 (5.7)	0.50
Lacunar	466 (19.7)	138 (21.2)	0.39
Antihypertensive intervention	1177 (49.7)	330 (50.7)	0.66
aPS, GPS*	4.7 (2.8–7.1)	16.0 (12.7–22.6)	<0.001
aCL, GPL*	5.0 (4.0–6.6)	8.1 (5.9–12.2)	<0.001

Data were presented as mean (SD) or n (%) unless otherwise noted. aCL indicates anticardiolipin antibodies; aPS, antiphosphatidyl serine antibodies; GPL, IgG anticardiolipin antibodies units; GPS, IgG antiphosphatidylserine antibodies units; and NIHSS, National Institutes of Health Stroke Scale (scores range from 0 to 42).
*Data were presented as median (interquartile range).
†Nine patients with both thrombotic and embolic subtypes; 64 patients with thrombotic and lacunar subtypes; 5 patients with embolic and lacunar subtypes; and 1 patient with all 3 subtypes.

Table 2. Odds Ratios or Hazard Ratios (95% Confidence Interval) of Clinical Outcomes According to aPS Status and 1 Interquartile Range
Outcomes	aPS Negative (n=2362)	aPS Positive (n=651)	Unadjusted Model		Multivariable Model 1		Multivariable Model 2		Multivariable Model 3
Outcomes	aPS Negative (n=2362)	aPS Positive (n=651)	OR or HR (95% CI)	P Value	OR or HR (95% CI)	P Value	OR or HR (95% CI)	P Value	OR or HR (95% CI)	P Value
Status
Death and major disability, n (%)*	562 (23.9)	189 (29.1)	1.30 (1.07–1.58)	0.008	1.24 (1.00–1.54)	0.05	1.35 (1.07–1.71)	0.01	1.38 (1.07–1.78)	0.01
Modified Rankin Scale, n (%)
0 (no symptoms)	434 (18.5)	121 (18.6)	1.81 (1.01–1.38)‡	0.04	1.07 (0.92–1.26)‡	0.23	1.08 (0.91–1.29)‡	0.36	1.07 (0.90–1.27)‡	0.48
1 (no significant disability)	811 (34.5)	198 (30.5)
2 (slight disability)	541 (23.0)	142 (21.9)
3 (moderate disability)	296 (12.6)	91 (14.0)
4 (moderately severe disability)	159 (6.8)	50 (7.7)
5 (severe disability)	51 (2.2)	21 (3.2)
6 (dead)	56 (2.4)	27 (4.2)
Death, n (%)	56 (2.4)	27 (4.2)	1.85 (1.16–2.93)	0.009	1.61 (1.01–2.57)	0.05	1.63 (0.99–2.69)	0.05	1.40 (0.83–2.36)	0.20
Major disability, n (%)	506 (21.6)	162 (24.9)	1.21 (0.99–1.48)	0.07	1.15 (0.92–1.43)	0.23	1.25 (0.98–1.59)	0.07	1.24 (0.97–1.59)	0.09
Recurrent stroke, n (%)	45 (1.9)	9 (1.4)	0.76 (0.37–1.56)	0.46	0.75 (0.36–1.54)	0.43	0.65 (0.30–1.41)	0.28	0.67 (0.31–1.45)	0.31
Vascular events,† n (%)	64 (2.7)	20 (3.1)	1.12 (0.67–1.87)	0.67	1.03 (0.61–1.73)	0.91	0.97 (0.56–1.68)	0.90	0.98 (0.56–1.72)	0.94
Per interquartile range
Death and major disability*	…	…	1.07 (1.01–1.14)	0.02	1.04 (0.98–1.12)	0.22	1.10 (1.01–1.20)	0.03	1.10 (1.01–1.21)	0.03
Ordinal modified Rankin Scale	…	…	1.07 (1.02–1.13)‡	0.004	1.04 (0.99–1.09)‡	0.23	1.05 (0.99–1.12)‡	0.09	1.03 (0.97–1.10)‡	0.33
Death	…	…	1.18 (1.08–1.30)	0.001	1.15 (1.04–1.27)	0.008	1.19 (1.05–1.35)	0.007	1.09 (0.97–1.23)	0.16
Major disability	…	…	1.04 (0.98–1.11)	0.21	1.01 (0.94–1.08)	0.86	1.05 (0.96–1.14)	0.29	1.04 (0.95–1.14)	0.38
Recurrent stroke	…	…	0.98 (0.79–1.22)	0.86	0.97 (0.78–1.21)	0.80	0.91 (0.70–1.17)	0.45	0.91 (0.70–1.17)	0.44
Vascular events†	…	…	1.07 (0.93–1.23)	0.35	1.04 (0.91–1.21)	0.55	1.02 (0.85–1.22)	0.83	1.00 (0.84–1.19)	0.98

Multivariable model 1: adjusted for age, sex, baseline NIHSS scores (>4 versus ≤4), time from onset to hospitalization, systolic blood pressure at entry, smoking, drinking, ischemic stroke subtypes, diabetes mellitus, antihypertensive intervention versus control. Model 2: model 1 plus anticardiolipin antibodies; model 3: model 2 with NIHSS adjusted as a continuous variable. aPS indicates antiphosphatidylserine antibodies; CI, confidence interval; HR, hazard ratio; OR, odds ratio; and NIHSS, National Institutes of Health Stroke Scale.
*Modified Rankin Scale score of 3–6.
†Include vascular deaths, nonfatal stroke, nonfatal myocardial infarction, hospitalized and treated angina, hospitalized and treated congestive heart failure, and hospitalized and treated peripheral arterial disease.
‡Odds of a 1-U higher modified Rankin Scale score.

Table 3. Reclassification and Discrimination Statistics for Clinical Outcomes by Serum Antiphosphatidylserine Antibodies Among Patients With Acute Ischemic Stroke
	NRI (Category Free), %		NRI (Category), %*		IDI, %
	Estimate (95% CI)	P Value	Estimate (95% CI)	P Value	Estimate (95% CI)	P Value
Death and major disability†
Conventional model‡
Conventional model+aPS positive	10.9 (3.8 to 17.9)	0.002	1.8 (0.6 to 3.1)	0.004	0.2 (0.01 to 0.3)	0.04
Conventional model+aPS titer	11.3 (3.2 to 19.3)	0.006	0.8 (−0.3 to 1.9)	0.14	0.2 (−0.01 to 0.3)	0.06
Death
Conventional model‡
Conventional model+aPS positive	21.3 (0.9 to 41.7)	0.04	3.8 (−2.4 to 10.0)	0.23	0.2 (−0.1 to 0.6)	0.23
Conventional model+aPS titer	15.8 (−5.9 to 37.4)	0.15	3.8 (−1.4 to 9.1)	0.15	0.4 (−0.2 to 0.9)	0.18
Major disability
Conventional model‡
Conventional model+aPS positive	8.1 (0.8 to 15.4)	0.03	1.5 (0.2 to 2.7)	0.02	0.09 (−0.02 to 0.2)	0.10
Conventional model+aPS titer	4.9 (−3.5 to 13.3)	0.25	0.8 (−0.2 to 1.7)	0.12	0.04 (−0.02 to 0.1)	0.23

aPS indicates antiphosphatidylserine antibodies; CI, confidence interval; IDI, integrated discrimination index; and NRI, net reclassification improvement.
*Patients were divided into 3 categories for the risk classification: <5%, 5% to 15%, and >15%.
†Modified Rankin Scale score of 3–6.
‡Conventional model included age, sex, National Institutes of Health Stroke Scale scores, time from stroke onset to hospital, systolic blood pressure, current smoking, current drinking, ischemic stroke subtypes, diabetes mellitus, and anticardiolipin antibodies.